Abstract The goal of the proposed research is to identify novel mechanisms that regulate airway inflammation and remodeling in severe asthma. Group 2 innate lymphoid cells (ILC2s) and CD4+ Th2 cells are thought to promote airway inflammation in a large subset of severe asthmatics and novel molecules that control both ILC2s and Th2 cells, as well as airway smooth muscle (ASM) remodeling, may represent therapeutic targets. We have identified a novel bidirectional pathway in lung inflammation and remodeling regulated by the ligand/receptor pair ALCAM (expressed on smooth muscle) and CD6 (expressed on ILC2s and Th2 cells). We hypothesize that ALCAM expressed on lung structural cells (smooth muscle) and CD6 expressed on ILC2 and Th2 cells may be a novel pathway to drive both pro- inflammatory responses as well as tissue remodeling. We will perform in vitro studies with human lung, lung lymph node, and peripheral blood ILC2s and Th2 cells stimulated with ALCAM-Fc (that stimulates CD6) or ALCAM-expressing ASM cells and measure ILC2 and Th2 cell cytokine production and proliferation. Further, we will culture human ASM cells with CD6-Fc (that stimulates ALCAM) as well as CD6-expressing lymphocytes and determine levels of hyperplasia/hypertrophy and inflammatory mediator expression. Tissue and airway samples from asthmatics and controls will be assessed for levels of CD6 expression on ILC2s and Th2 cells, as well as ALCAM expression on ASM. Finally, we will use innate and chronic allergen challenge models with CD6 knockout mice to test the role of CD6 in ILC2/Th2 cell proliferation and cytokine production as well as airway smooth muscle remodeling, lung inflammation, and hyperresponsiveness. As anti-CD6 therapy has shown safety and efficacy in other human immune diseases including severe psoriasis, our studies to uncover the mechanisms of ALCAM/CD6 interactions in asthma may lead to a novel therapeutic strategy for severe asthma.